Neurocognitive impairment is a devastating consequence of HIV-1 infection. The proposed research will apply complementary viral dynamic, cellular immunology, and neuroimaging approaches to investigate relationships between intrathecal viral replication, anti-HIV cytotoxic T lymphocyte (CTL) responses, microglial activation/proliferation, and neuronal loss in persons living with HIV. We previously demonstrated discordant viral decay in cerebrospinal fluid (CSF) and plasma in subjects initiating antiretroviral therapy, providing evidence that CSF virus arose, at least in part, from an intrathecal source. Although anti-HIV CTL are critical for controlling HTV-1 replication in peripheral tissues, their role in the CNS is not well understood. Specific aims will investigate AIDS neuropathogenesis through several hypotheses. To assess the extent of intrathecal viral replication and its association with stage of HIV-1 disease we will quantify viral decay in CSF and plasma during initiation of potent antiretroviral therapy in a cohort of HlV-infected adults, to include mathematical modeling in some subjects. We expect intrathecal viral replication to be associated with more advanced HIV disease and neurocognitive impairment. We will also characterize anti-HIV CTL responses in CSF and peripheral blood using advanced flow cytometry techniques, and will assess whether these responses are compartmentalized. We hypothesize that weak intrathecal anti-HIV CTL responses allow vigorous viral replication during advanced HIV disease, and predict progressively discordant HIV epitope recognition in CSF and peripheral blood during advanced HIV disease and associated neurocognitive impairment. It is less likely that advanced HIV disease will be associated with more vigorous intrathecal anti-HIV CTL responses, immune activation and neurocognitive impairment, although this is also plausible. In addition, we will assess whether loss of blood-brain barrier integrity, microglial activation/proliferation, and neuronal dropout as assessed by MRI and MRS imaging are associated with intrathecal viral replication and weaker intrathecal anti-HIV CTL responses. Cells expanded ex vivo and other specimens will be cryopreserved for unplanned analyses. These studies will help define the extent to which HIV associated CNS dysfunction reflects the interplay between intrathecal viral replication, specific anti-HIV cellular immune responses, and immune activation. Characterizing these relationships will expand our knowledge regarding key events that lead to AIDS dementia, and may suggest novel approaches to other immunologic or viral-mediated diseases that affect the brain.